PROJECT SUMMARY The medial nucleus of the trapezoid body (MNTB) plays a key role in sound localization by delivering fast and precise synaptic inhibition to auditory neurons in the mammalian brainstem. Previous studies indicate that activity-dependent mechanisms are involved in the refinement of this auditory pathway during early development. However, a fundamental issue that remains puzzling concerns the nature of the activity, since the refinement begins before the onset of hearing. We have identified spontaneous burst firing as the major form of spontaneous electrical activity before hearing onset. The major goal of this proposal is to use innovative electrophysiological and imaging techniques to determine the cellular and synaptic mechanisms of activity-dependent development in the MNTB in vivo. In the first aim, we will study the mechanisms that underlie bursting activity. Using electrophysiological techniques we will test the role of different types of synapses in bursting activity. For example, we predict that antagonists of synaptic transmission will block bursting activity during early postnatal development. In additional electrophysiological and immunostaining experiments we will study the developmental properties and roles of the voltage-activated conductance Ih, which could be involved in the fine tuning of electrical properties of MNTB cells and their responses to synaptic stimulation. In the second aim we will use two-photon calcium imaging to measure the activity of cellular ensembles in the MNTB of prehearing rats. We will validate this approach with electrophysiology experiments and will describe the spatial and temporal properties of the spontaneous ensemble activity, and how these patterns change during postnatal development. Finally, in the third aim, and in collaboration with Drs. Peqa, Tchernikovsky and Smotherman we will use similar methods described in the first and second aims in combination with sound stimulation to determine the responses of MNTB ensembles to simple and complex sounds. By manipulating the spectral content of sound stimuli we will study the capacity and limitations for short-term adaptation in the mammalian brainstem. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Tinnitus, a prevalent and poorly understood condition where sounds are perceived in the absence of auditory stimulation affects ~20% of Americans, and has debilitating effects in as many as 2 million citizens. Our experiments will directly determine how parts of the auditory system activate in the absence of sound, and could help explain why some people hear sounds when they shouldn't.